Safety and Tolerability Study of Allogeneic Mesenchymal Stem Cell Infusion in Adults With Cystic Fibrosis

A Phase I, Single Center, Open Label, Single Dose, Dose Escalation Study Assessing the Safety and Tolerability of AllogeneiC MEsenchymAl Stem CEll Infusion in Adults With Cystic Fibrosis-CEASE CF

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02866721

Acronym

CEASE-CF

Enrollment

Registered

2016-08-15

Start date

2016-08-31

Completion date

2020-08-31

Last updated

2023-01-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cystic Fibrosis

Keywords

Human Mesenchymal Stem Cells

Brief summary

This study is being done to test if it is safe to give stem cells to adult patients with Cystic Fibrosis (CF). The kind of stem cells we are studying are called allogeneic human mesenchymal stem cells or MSCs. MSCs are cells in the body that can grow into different types of cells and respond to various environmental situations. Allogeneic means the cells come from another person (a donor). This study is only looking at whether or not it is safe to give the stem cells to adults with CF and how the infusion is tolerated. In the future, other studies may be done to see if stem cells can be a new therapeutic treatment for CF. Stem cells, like other medical products that are intended to treat, cure or prevent disease, generally require approval from the U.S. Food and Drug Administration (FDA) before they can be marketed. The FDA has not approved any stem cell-based products for usual medical care, other than some specific blood forming stem cells for certain indications.

Detailed description

This will be a prospective, single-center, dose-escalation, open-label interventional study to evaluate the safety and tolerability of allogeneic human mesenchymal stem cells (hMSCs) in 15 clinically stable subjects with cystic fibrosis (CF) age ≥ 18 years. After a two to six week screening period, subjects will have a Baseline visit (Days 1-2) where they will undergo a single intravenous infusion of up to 5 x 10E6 allogeneic hMSCs/kilogram (hMSCs/kg) of body weight. Infusions will be performed in the Dahms Clinical Research Unit (DCRU) of University Hospitals Cleveland Medical Center. Subjects will be monitored for any infusion related toxicities for 24 hours after the infusion. Subsequent study visits will occur on Days 7, 14, 28, Months 3 and 6 and telephone calls will occur on Days 4 (or 5), 21, 56 and Month 12. Subject safety and tolerability of a single dose of hMSCs will be evaluated at study visits by review of subject diaries, interval history, pulmonary exacerbations, physical examination, spirometry, and analysis of safety laboratories. Special attention will be placed upon detecting pulmonary exacerbations because anti-inflammatory therapies theoretically could suppress the immune system to the point where it leads to increased infectious complications, although MSC therapeutics are proposed to be antimicrobial. In addition to evaluating safety, this study will also explore efficacy end-points for future clinical trials of MSCs in CF including inflammatory biomarkers from blood and sputum. Serum markers (calprotectin, myeloperoxidase (MPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1β (IL-1β), IL-6, IL8, IL-17, and tumor necrosis factor-a (TNF-a) and sputum markers (white cell counts and differentials, IL-1β, IL-6, IL-8, IL-10, IL-17, GM-CSF, macrophage inflammatory protein-3a (MIP- 3a), TNF-a, and active proteases including neutrophil elastase, alpha-1-antitrypsin, and matrix metallopeptidase 9 (MMP-9) will be determined at Baseline and on Days 7 and 28 for with-in subject comparison. All subject samples will be archived for future projects. Finally, a diagnostic bone marrow exam will be performed on subjects with CF who consent to undergo this optional procedure. Bone marrow samples will be banked and used for future translational studies.

Interventions

BIOLOGICALMesenchymal Stem Cells

A single dose, one time infusion (in the vein) of one of the following doses of human mesenchymal stem cells (hMSCs): 1 x 10\^6, 3 x 10\^6 or 5 x 10\^6 human mesenchymal stem cells per kilogram body weight (hMSCs/kg) during Visit 2. A traditional 3+3 design will be utilized. Allogeneic mesenchymal stem cells (MSCs) will be derived from bone marrow aspirates from a healthy donor whose serum tests negative for cytomegalovirus (CMV) antibodies. Healthy donors will undergo tests for infectious disease and screening for 41 common cystic fibrosis transmembrane conductance regulator (CFTR) mutations. In addition, the MSCs will be validated for in vitro and in vivo efficacy and potency using the in vivo murine pre-clinical model of cystic fibrosis lung infection and inflammation.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Yes

Inclusion criteria

Cystic Fibrosis (CF) Subject Inclusion Criteria: 1. Male or female ≥18 years of age 2. Confirmed diagnosis of CF as evidenced by 1 or more clinical features consistent with the CF phenotype and 1 or more of the following criteria: 1. Sweat chloride equal to or greater than 60 milliequivalents per liter (mEq/L) by quantitative pilocarpine iontophoresis test (QPIT) 2. 2 well-characterized, disease causing mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene 3. Clinically stable with no significant changes in health status within 2 weeks prior to screening. 4. Forced expiratory volume in the first second (FEV1) ≥ 40% predicted for age based on the global lung function initiative equations at the screening visit 5. Weight ≥ 40 kilograms at the screening visit 6. Able to perform repeatable, consistent efforts in pulmonary function testing 7. Written informed consent obtained from the subject. CF Subject

Exclusion criteria

1. Use of an investigational agent within the 4-week period prior to Visit 1 (Day -42 to -10) 2. Chronic daily (\>10 mg) or alternate daily (\>20 mg on alternate days) use of systemic corticosteroids within the 4 weeks prior to Visit 1 (Day -42 to -10) or initiation of any dosage of systemic corticosteroids within 72 hours prior to Visit 2 (Day 1). 3. Use of hydroxychloroquine or immunosuppressants. 4. Initiation of a new antibiotic (oral, intravenous, and/or inhaled) that is not part of the subject's maintenance regimen for treatment of acute respiratory symptoms within 2 weeks prior to screening through Visit 2 (Day 1) 5. Initiation of any new chronic therapy (e.g., Pulmozyme®, hypertonic saline, Kalydeco®, Orkambi®, high-dose ibuprofen azithromycin, TOBI®, Cayston®, nebulized colistiin, bronchodilators, inhaled corticosteroids, etc.) within 4 weeks prior to screening 6. Active treatment for non-tuberculous Mycobacteria 7. History of a sputum culture positive for a Burkholderia cepacia complex organism in the previous 12 months. 8. Current tobacco smoker 9. Oxygen saturation \< 92% on room air at Visit 1 (Day -42 to -10) 10. History of pulmonary hypertension 11. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2.5 times the upper limit of normal at screening, documented biliary cirrhosis, or portal hypertension 12. Total bilirubin concentration \> 1.2 milligram per deciliter (mg/dL) at screening 13. Creatinine \> 1.8 mg/dL at screening 14. Pregnant, breastfeeding, or unwilling to practice birth control between Visit 2 (Day 1) and Telephone Call 3 (Day 56) (acceptable forms of contraception: abstinence, hormonal birth control, intrauterine device, or barrier method plus a spermicidal agent), unless surgically sterilized or postmenopausal 15. Screening hematology with white blood cell count \< 4.5 x 109 cells/liter, hematocrit \< 30%, and platelets \< 150 x 109 platelets/liter 16. History of invasive cancer requiring systemic therapy 17. History of organ transplantation 18. Currently listed for lung transplantation or having potential to be listed for lung transplantation in the succeeding 12 calendar months from screening 19. Subject unlikely to complete the study as determined by the Investigator Inclusion Criteria for Healthy Volunteer Donors (NOTE: Enrollment for Healthy Volunteers is closed): 1. Male/female age ≥ 18 years to ≤ 40 years 2. Able to understand and sign consent form (a legally authorized representative will not be permitted) Inclusion Criteria for CF Donors: 1\. CF subject enrolled in the main study and consented to this optional procedure

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With a Dose Limiting Toxicity (DLT), Triggered by Occurrence in the First 24 Hours After Human Mesenchymal Stem Cell (hMSC) Infusion of Grade ≥3 Infusion-related Allergic Toxicities	24 hours post infusion	For this study, dose limiting toxicities included the emergence of infusion-related allergic adverse events as well as regimen related toxicities in the first 24 hours after hMSC infusion of a grade ≥ 3 as scored according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. This is the number of participants who experienced a dose limiting toxicity during the study.
Number of Serious Adverse Events and Number of Non-Serious Adverse Events	1 year	Participants were followed for 12 months after human mesenchymal stem cell infusion. All events from the infusion date through the end of follow-up were included. This shows the total number of adverse events or serious adverse events occurring in each dosing cohort.
Number of Pulmonary Exacerbations Requiring Intravenous Antibiotics	1 year	Participants were followed for 12 months after human mesenchymal stem cell infusion. All events occurring from the infusion date through the end of follow-up were included. This shows the number of pulmonary exacerbations requiring intravenous antibiotics in each dosing cohort.
Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	Baseline and 30 minutes, 4 hours, 24 hours, 7 days, 14 days, 28 days, 3 months, 6 months Post Human Mesenchymal Stem Cell Infusion	Lung function was followed for 6 months post human mesenchymal stem cell infusion. This shows the mean forced expiratory volume in the first second (FEV1) percent predicted for each cohort throughout the study.

Secondary

Measure	Time frame	Description
Serum Inflammatory Markers - Calportectin Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Serum inflammatory markers including Calprotectin were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit for detection for calportectin was 88.3 picogram per millilitre.
Serum Inflammatory Markers - Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Serum inflammatory markers including Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit for detection for GM-CSF was 2.6 picograms per milliliter.
Serum Inflammatory Markers - Interleukin-1 (IL-1) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Serum inflammatory markers including interleukin -1 (IL-1) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit for detection for IL-1 was 13.1 picograms per milliliter.
Serum Inflammatory Markers - Interleukin-17 (IL-17) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Serum inflammatory markers including interleukin -17 (IL-17) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit for detection for IL-17 was 13.5 picograms per milliliter.
Serum Inflammatory Markers - Interleukin-6 (IL-6) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Serum inflammatory markers including interleukin -6 (IL-6) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit for detection for IL-6 was 13.5 picograms per milliliter.
Serum Inflammatory Markers - Interleukin-8 (IL-8) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Serum inflammatory markers including interleukin -8 (IL-8) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit for detection for IL-8 was 13.9 picograms per milliliter.
Serum Inflammatory Markers - Myeloperoxidase (MPO) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Serum inflammatory markers including myeloperoxidase (MPO) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown.
Serum Inflammatory Markers - Tumor Necrosis Factor Alpha (TNF-a) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Serum inflammatory markers including tumor necrosis factor alpha (TNF-a) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit of detection for TNF-a was 12.9 picograms per millilter.
Sputum Inflammatory Markers - Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Sputum inflammatory markers including granulocyte-macrophage colony-stimulating factor (GM-CSF) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.
Sputum Inflammatory Markers - Interleukin-1 (IL-1) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Sputum inflammatory markers including interleukin-1 (IL-1) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.
Sputum Inflammatory Markers - Interleukin-10 (IL-10) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Sputum inflammatory markers including interleukin-10 (IL-10) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.
Sputum Inflammatory Markers - Interleukin-17 (IL-17) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Sputum inflammatory markers including interleukin-17 (IL-17) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.
Sputum Inflammatory Markers - Interleukin-6 (IL-6) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Sputum inflammatory markers including interleukin-6 (IL-6) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.
Sputum Inflammatory Markers - Interleukin-8 (IL-8) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Sputum inflammatory markers including interleukin-8 (IL-8) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.
Sputum Inflammatory Markers - Macrophage Inflammatory Protein-3 Alpha (MIP-3a) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Sputum inflammatory markers including macrophage inflammatory protein-3 alpha (MIP-3a) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.
Sputum Inflammatory Markers - Tumor Necrosis Factor Alpha (TNF-a) Measurements at Baseline, Day 7, and Day 28	Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion	Sputum inflammatory markers including tumor necrosis factor alpha (TNF-a) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.

Countries

United States

Participant flow

Participants by arm

Arm	Count
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram One time intravenous Infusion of up to 5 x 10\^6 allogeneic human mesenchymal stem cells per kilogram body weight (hMSCs/kg). A dose escalation using the 3+3 design was employed. The three doses were 1 x 10\^6, 3 x 10\^6, and 5 x 10\^6 hMSCs/kg. There was no placebo group. All study participants received stem cells. Mesenchymal Stem Cells (MSCs): A single dose, one time infusion (in the vein) of one of the following doses of hMSCs: 1 x 10\^6, 3 x 10\^6 or 5 x 10\^6 hMSCs/kg body weight during Visit 2. A traditional 3+3 design was utilized. Allogeneic MSCs were derived from bone marrow aspirates from a healthy donor whose serum tested negative for cytomegalovirus (CMV) antibodies. The healthy donor underwent tests for infectious disease and screening for 41 common cystic fibrosis transmembrane conductance regulator (CFTR) mutations. In addition, the MSCs were validated for in vitro and in vivo efficacy and potency using the in vivo murine pre-clinical model of cystic fibrosis (CF) lung infection and inflammation.	3
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram One time intravenous Infusion of up to 5 x 10\^6 allogeneic human mesenchymal stem cells per kilogram body weight (hMSCs/kg). A dose escalation using the 3+3 design was employed. The three doses were 1 x 10\^6, 3 x 10\^6, and 5 x 10\^6 hMSCs/kg. There was no placebo group. All study participants received stem cells. Mesenchymal Stem Cells (MSCs): A single dose, one time infusion (in the vein) of one of the following doses of hMSCs: 1 x 10\^6, 3 x 10\^6 or 5 x 10\^6 hMSCs/kg body weight during Visit 2. A traditional 3+3 design was utilized. Allogeneic MSCs were derived from bone marrow aspirates from a healthy donor whose serum tested negative for cytomegalovirus (CMV) antibodies. The healthy donor underwent tests for infectious disease and screening for 41 common cystic fibrosis transmembrane conductance regulator (CFTR) mutations. In addition, the MSCs were validated for in vitro and in vivo efficacy and potency using the in vivo murine pre-clinical model of cystic fibrosis (CF) lung infection and inflammation.	3
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram One time intravenous Infusion of up to 5 x 10\^6 allogeneic human mesenchymal stem cells per kilogram body weight (hMSCs/kg). A dose escalation using the 3+3 design was employed. The three doses were 1 x 10\^6, 3 x 10\^6, and 5 x 10\^6 hMSCs/kg. There was no placebo group. All study participants received stem cells. Mesenchymal Stem Cells (MSCs): A single dose, one time infusion (in the vein) of one of the following doses of hMSCs: 1 x 10\^6, 3 x 10\^6 or 5 x 10\^6 hMSCs/kg body weight during Visit 2. A traditional 3+3 design was utilized. Allogeneic MSCs were derived from bone marrow aspirates from a healthy donor whose serum tested negative for cytomegalovirus (CMV) antibodies. The healthy donor underwent tests for infectious disease and screening for 41 common cystic fibrosis transmembrane conductance regulator (CFTR) mutations. In addition, the MSCs were validated for in vitro and in vivo efficacy and potency using the in vivo murine pre-clinical model of cystic fibrosis (CF) lung infection and inflammation.	8
Total	14

Baseline characteristics

Characteristic	1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	3 Participants	3 Participants	8 Participants	14 Participants
Age, Continuous	28.3 years STANDARD_DEVIATION 10.7	28.0 years STANDARD_DEVIATION 4.7	31.7 years STANDARD_DEVIATION 12.7	30.2 years STANDARD_DEVIATION 10.6
Body Mass Index (BMI)	21.3 kg/m^2 STANDARD_DEVIATION 4.7	22.2 kg/m^2 STANDARD_DEVIATION 3.3	24.3 kg/m^2 STANDARD_DEVIATION 4.9	23.2 kg/m^2 STANDARD_DEVIATION 4.4
Forced Expiratory Volume in the first second (FEV1) % Predicted Distribution <70%	0 Participants	2 Participants	3 Participants	5 Participants
Forced Expiratory Volume in the first second (FEV1) % Predicted Distribution >=70-84%	1 Participants	0 Participants	2 Participants	3 Participants
Forced Expiratory Volume in the first second (FEV1) % Predicted Distribution >=85%	2 Participants	1 Participants	3 Participants	6 Participants
Genotype F508del Heterozygous	1 Participants	2 Participants	4 Participants	7 Participants
Genotype F508del Homozygous	1 Participants	0 Participants	3 Participants	4 Participants
Genotype Other	1 Participants	1 Participants	1 Participants	3 Participants
Height	167.8 cm STANDARD_DEVIATION 1.6	169.6 cm STANDARD_DEVIATION 18.7	173.6 cm STANDARD_DEVIATION 8.6	171.5 cm STANDARD_DEVIATION 10
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	3 Participants	2 Participants	8 Participants	13 Participants
Region of Enrollment United States	3 Participants	3 Participants	8 Participants	14 Participants
Sex: Female, Male Female	1 Participants	1 Participants	2 Participants	4 Participants
Sex: Female, Male Male	2 Participants	2 Participants	6 Participants	10 Participants
Sweat Chloride at Diagnosis	107.0 mmol/L STANDARD_DEVIATION 7.5	82.7 mmol/L STANDARD_DEVIATION 26.6	99.4 mmol/L STANDARD_DEVIATION 20.8	97.3 mmol/L STANDARD_DEVIATION 20.6
Weight	60.1 kg STANDARD_DEVIATION 13.8	63.2 kg STANDARD_DEVIATION 7.4	73.0 kg STANDARD_DEVIATION 14.1	68.2 kg STANDARD_DEVIATION 13.4

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 3	0 / 3	0 / 8
other Total, other adverse events	2 / 3	2 / 3	8 / 8
serious Total, serious adverse events	2 / 3	2 / 3	2 / 8

Outcome results

Primary

Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.

Lung function was followed for 6 months post human mesenchymal stem cell infusion. This shows the mean forced expiratory volume in the first second (FEV1) percent predicted for each cohort throughout the study.

Time frame: Baseline and 30 minutes, 4 hours, 24 hours, 7 days, 14 days, 28 days, 3 months, 6 months Post Human Mesenchymal Stem Cell Infusion

Population: All subjects who received human mesenchymal stem cells were included in the analysis.

Arm	Measure	Group	Value (MEAN)	Dispersion
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 24 hours post infusion	86.4 FEV1 percent predicted	Standard Deviation 15.6
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 6 months post infusion	91.3 FEV1 percent predicted	Standard Deviation 18.7
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 14 days post infusion	85.6 FEV1 percent predicted	Standard Deviation 8
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 7 days post infusion	83.6 FEV1 percent predicted	Standard Deviation 4.3
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 at baseline	83.2 FEV1 percent predicted	Standard Deviation 8.5
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 3 months post infusion	89.4 FEV1 percent predicted	Standard Deviation 17.2
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 4 hours post infusion	83.1 FEV1 percent predicted	Standard Deviation 14.3
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 30 minutes post infusion	79.7 FEV1 percent predicted	Standard Deviation 9.9
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 28 days post infusion	85.4 FEV1 percent predicted	Standard Deviation 11.4
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 7 days post infusion	64.5 FEV1 percent predicted	Standard Deviation 9.8
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 at baseline	71.4 FEV1 percent predicted	Standard Deviation 13.5
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 30 minutes post infusion	69.0 FEV1 percent predicted	Standard Deviation 9.6
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 4 hours post infusion	69.0 FEV1 percent predicted	Standard Deviation 14.2
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 24 hours post infusion	75.1 FEV1 percent predicted	Standard Deviation 13.7
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 14 days post infusion	67.5 FEV1 percent predicted	Standard Deviation 8.4
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 28 days post infusion	69.8 FEV1 percent predicted	Standard Deviation 12
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 3 months post infusion	70.9 FEV1 percent predicted	Standard Deviation 14.2
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 6 months post infusion	70.0 FEV1 percent predicted	Standard Deviation 11.1
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 4 hours post infusion	75.2 FEV1 percent predicted	Standard Deviation 21.1
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 at baseline	77.7 FEV1 percent predicted	Standard Deviation 20.2
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 28 days post infusion	77.8 FEV1 percent predicted	Standard Deviation 19.7
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 30 minutes post infusion	75.3 FEV1 percent predicted	Standard Deviation 20.3
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 6 months post infusion	76.1 FEV1 percent predicted	Standard Deviation 20.7
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 7 days post infusion	76.5 FEV1 percent predicted	Standard Deviation 18.7
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 24 hours post infusion	77.4 FEV1 percent predicted	Standard Deviation 21.2
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 3 months post infusion	76.1 FEV1 percent predicted	Standard Deviation 19.5
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.	FEV1 14 days post infusion	75.6 FEV1 percent predicted	Standard Deviation 19.9

Primary

Number of Participants With a Dose Limiting Toxicity (DLT), Triggered by Occurrence in the First 24 Hours After Human Mesenchymal Stem Cell (hMSC) Infusion of Grade ≥3 Infusion-related Allergic Toxicities

For this study, dose limiting toxicities included the emergence of infusion-related allergic adverse events as well as regimen related toxicities in the first 24 hours after hMSC infusion of a grade ≥ 3 as scored according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. This is the number of participants who experienced a dose limiting toxicity during the study.

Time frame: 24 hours post infusion

Population: Number of participants with a dose limiting toxicity. All subjects receiving the human mesenchymal stem cell infusing were included.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Number of Participants With a Dose Limiting Toxicity (DLT), Triggered by Occurrence in the First 24 Hours After Human Mesenchymal Stem Cell (hMSC) Infusion of Grade ≥3 Infusion-related Allergic Toxicities	0 Participants
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Number of Participants With a Dose Limiting Toxicity (DLT), Triggered by Occurrence in the First 24 Hours After Human Mesenchymal Stem Cell (hMSC) Infusion of Grade ≥3 Infusion-related Allergic Toxicities	0 Participants
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Number of Participants With a Dose Limiting Toxicity (DLT), Triggered by Occurrence in the First 24 Hours After Human Mesenchymal Stem Cell (hMSC) Infusion of Grade ≥3 Infusion-related Allergic Toxicities	0 Participants

Primary

Number of Pulmonary Exacerbations Requiring Intravenous Antibiotics

Participants were followed for 12 months after human mesenchymal stem cell infusion. All events occurring from the infusion date through the end of follow-up were included. This shows the number of pulmonary exacerbations requiring intravenous antibiotics in each dosing cohort.

Time frame: 1 year

Population: All subjects who received human mesenchymal stem cells were included in the analysis.

Arm	Measure	Value (NUMBER)
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Number of Pulmonary Exacerbations Requiring Intravenous Antibiotics	2 pulmonary exacerbations
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Number of Pulmonary Exacerbations Requiring Intravenous Antibiotics	3 pulmonary exacerbations
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Number of Pulmonary Exacerbations Requiring Intravenous Antibiotics	2 pulmonary exacerbations

Primary

Number of Serious Adverse Events and Number of Non-Serious Adverse Events

Participants were followed for 12 months after human mesenchymal stem cell infusion. All events from the infusion date through the end of follow-up were included. This shows the total number of adverse events or serious adverse events occurring in each dosing cohort.

Time frame: 1 year

Population: All subjects who received human mesenchymal stem cells were included in the analysis.

Arm	Measure	Group	Value (NUMBER)
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Number of Serious Adverse Events and Number of Non-Serious Adverse Events	Serious Adverse Event	3 number of adverse events
1 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Number of Serious Adverse Events and Number of Non-Serious Adverse Events	Non-Serious Adverse Event	16 number of adverse events
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Number of Serious Adverse Events and Number of Non-Serious Adverse Events	Serious Adverse Event	3 number of adverse events
3 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Number of Serious Adverse Events and Number of Non-Serious Adverse Events	Non-Serious Adverse Event	31 number of adverse events
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Number of Serious Adverse Events and Number of Non-Serious Adverse Events	Serious Adverse Event	3 number of adverse events
5 x 10^6 Human Allogeneic Mesenchymal Stem Cells Per Kilogram	Number of Serious Adverse Events and Number of Non-Serious Adverse Events	Non-Serious Adverse Event	68 number of adverse events

Secondary

Serum Inflammatory Markers - Calportectin Measurements at Baseline, Day 7, and Day 28

Serum inflammatory markers including Calprotectin were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit for detection for calportectin was 88.3 picogram per millilitre.